Cognitive Behavioral Therapy for Veterans With Comorbid Posttraumatic Headache and Posttraumatic Stress Disorder Symptoms

This randomized clinical trial investigates if cognitive behavioral therapies for posttraumatic stress disorder (PTSD) and posttraumatic headache improve headache-related disability and PTSD symptom severity in US veterans compared with treatment per usual.

Background and rationale 55 Posttraumatic headache (PTHA) is a singularly unique and vexing by-product of traumatic brain injury (TBI) 56 offering numerous challenges both to the individuals experiencing them as well as the medical providers tasked 57 with treating this growing problem (Monteith et al., 2009). Although PTHA is not a new phenomenon (there are 58 reports of posttraumatic headache dating back to the 1700s), very little is known about headaches with onset or 59 exacerbation after TBI.

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Despite the significant incidence of PTHA among individuals who suffer TBI, very little is known about its 62 treatment. To date, there are few controlled studies of PTHA treatment, and the nesting of PTHA symptoms 63 within postconcussion syndrome makes this population unresponsive to typical primary headache medications. 64 Many PTHA sufferers attempt self-treatment through the use of acetaminophen, ibuprofen, and opiate/triptan 65 medication (usually prescribed for other reasons). Unfortunately, these over-the-counter or self-prescribed The primary aim of the study is to compare two talk therapies, an eight session CBT intervention for headaches Hypothesis 1. The CBTH, CPT, and TAU interventions differ in a statistically significant degree in headache 107 disability at posttreatment, measured by the HIT-6. Where μ CBTH, μ CPT and μ TAU represent the adjusted mean 108 HIT-6 scores at posttreatment, adjusted by HIT-6 scores measured at baseline.

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Only if the null hypothesis is rejected, two planned comparisons will be conducted among selected arms: Only if the null hypothesis is rejected, two planned comparisons will be conducted among selected arms: There are two secondary objectives. The first objective is to determine whether the CBTH group, compared to 151 the CPT group, results in a greater decrease in HIT-6 and PTSD scores. The second objective is to assess 152 between group differences related to longitudinal change in average headache frequency, reported twice daily 153 over a 14-day period as a secondary outcome. Participants will be asked to report the number of headaches they 154 had experienced since the last reporting period.

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Comparison Between CBTH and CPT 157 As secondary analyses, the CBTH intervention will be directly compared to the CPT intervention on the 158 primary outcomes.  following military deployment and combat trauma. Clinic-based assessments will occur prior to treatment and 1-

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, 3-, and 6-months (following treatment completion). Blood will be collected prior to treatment, during two of the Two co-primary outcomes are defined that measure headache disability and PTSD symptoms.

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Secondary Outcomes

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Because this trial will be conducted under the auspices of the Consortium to Alleviate PTSD (CAP), a well-295 validated, standardized battery of secondary assessments will be administered as CAP common data elements.

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See Appendix for a comprehensive list of the domains and measures.

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Patient characteristics will be evaluated that clearly define the population being examined, including 301 demographic information (e.g., age, gender, race/ethnicity, education, employment and household income). No 302 information will be reported or displayed that allow identification of the individual participants.

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Ancillary Patient Characteristics

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Patient characteristics unrelated to basic demographic information that help define the population will also be 307 evaluated. Because this is a veteran population, information pertaining to one's military service (e.g., military 308 service branch, years in the service, and number of deployments) will be presented. Mental and physical health 309 information, such as medication use, diagnoses, comorbid symptoms of anxiety, depression, and problems with 310 sleep will also be presented. Depending on variable distributions, means, standard deviations, frequencies,

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and/or range of values will be presented. Additionally, treatment group imbalances will be evaluated using 312 absolute standard differences (ASD).

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Sample Size 315 A recent study helped to guide a determination of what constitutes a clinically meaningful change in perceived 316 headache disability and the proposed study is powered in light of these insights. In the primary care setting, 317 headache impact test (HIT-6) changes of 2.5 points (95% CI: -3.3 to -1.7) were described as "somewhat better" 318 and changes of 5.9 (95% CI: -7.6 to -4.1) were described as "much better." We considered a meaningful change 319 as somewhere between these two global impressions and used this marker as an index of clinically significant 320 between-group differences. Our study is powered to detect an effect size of 2.8 points between groups after 321 controlling for baseline scores (i.e., a residualized change) and constitutes an effect that would be meaningful to 322 most headache sufferers. Because there are two primary outcomes, alpha level was set at α < .025 to prevent 323 Type I error (see Type-I error strategy, below).

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Assuming an alpha level of 0.025, group sample sizes of n = 64 (N = 192), and a moderate correlation between 326 the baseline scores and final endpoints (r = 0.50), we will have power = 0.80 to detect an effect size of d = 0.52 327 between both of the joint primary comparisons. In realistic terms, this will allow us to detect a change of 2.8 328 points on the HIT-6 between the active treatments and the control. Changes smaller than this magnitude are 329 unlikely to be clinically meaningful.

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Interim Analyses 332 333 There are no interim analyses planned. Confidential review by a Data Safety Monitoring Board (DSMB) will 334 occur routinely, and we will not apply stopping rules for futility or superiority.

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Ending the Trial 337 338 The trial will cease when targeted enrollment is obtained.

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Analysis Populations

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Planned analyses will include both intention to treat (ITT) and per protocol (PP) population sets. The primary 343 analysis will be conducted on a modified ITT set defined as randomized individuals who actually receive one or 344 more treatment sessions. The PP set will be restricted to those individuals who actually complete 75% or more 345 treatment sessions (6 sessions of CBTH and 9 sessions of CPT) and complete the relevant assessment 346 occasions. The primary and secondary analyses will be conducted on both the ITT and PP sets and sensitivity 347 analyses will estimate differences in primary and secondary outcomes conditional on the population. Statistical assumptions of each model will be considered, including distributions and variance of outcome 355 variables. Means, standard deviations, frequencies, histograms, and levels of skewness and kurtosis will be 356 considered in determining how best to represent variables of interest. If these assumptions are violated, which 357 may be assessed using prescribed tests for such violations, proper adjustments to the model will be considered.

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Also considered will be the particular nature of each variable of interest as it relates to the specific subject We have developed a plan, as part of this protocol, to contact participants who dropout from treatment or are 368 lost to follow-up to assess for reasons for data missingness and status of PTHA and PTSD symptoms at the time 369 of dropout contact. We will use data from this data recovery protocol to guide Multiple imputation (MI) of 370 missing data that will be used to obtain an intention to treat (ITT) philosophy and the multiply imputed set will 371 serve as the basis for the primary analysis. Missing data will be imputed multiple times (m = 5), conditional on 372 baseline participant characteristics, headache characteristics, and previous measures of the outcome variables.

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The combined results will be utilized in the final model, including all individuals who were allocated to a 374 treatment arm according to the ITT definition. The treatment effect estimates from the MI procedure will be 375 compared to single imputation and last observation carry forward to ensure robustness (Wright & Sim, 2003).

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Variables that are time variant (e.g., brief-inventory of psychosocial functioning) and invariant (e.g., number of 377 deployments) will be examined as to whether they differentially predict missingness and to assess whether the 378 missing at random assumption has been met (Enders, 2010). If the assumption has not been met, variables that 379 contribute to that violation will be included in the final sensitivity analysis.